Quantitative trait loci for sensitivity to acute ethanol and ethanol consummatory behaviors in rats

Abstract

Individuals with a low initial response to alcohol (i.e., ethanol) are at greater risk of developing alcohol abuse or dependence later in life. Similar to humans, individual differences in ethanol sensitivity also can be seen in rats, and several laboratories have used these individual differences to generate selectively bred rats that differ in acute ethanol sensitivity. We have worked with two sets of such rats (Inbred High or Low Alcohol Sensitivity strains, IHAS or ILAS, respectively; Inbred Alcohol Tolerant or Non-Tolerant strains, IAT and IANT, respectively) and have confirmed previously mapped quantitative trait loci (QTL) for these acute differences with the use of recombinant congenic lines; however, the relationship between acute sensitivity and ethanol drinking in these rats has yet to be determined. Thus, here we tested the hypothesis that QTLs underlying variation in initial low sensitivity to ethanol also will modulate variation in ethanol drinking behaviors. Separate groups of selectively inbred parent and congenic rats were tested for the loss of righting response (LORR) and also assessed for ethanol consummatory behavior using either operant self-administration or an intermittent-access two-bottle choice procedure. LORR testing confirmed the presence of a LORR duration QTL in all of the congenics; however, the lack of a corresponding difference in blood ethanol concentration at the regaining of the righting response suggests that these QTLs may be mediating a difference in ethanol metabolism rather than in neuronal sensitivity. IHAS/ILAS-derived congenic rats did not differ from parent rats at any point during operant self-administration. IAT/IANT-derived congenic rats showed small, but significant, increases in ethanol consumption relative to the parent strains only during the initial stages of operant self-administration. In contrast to operant testing, IHAS/ILAS-derived congenic rats showed significantly greater ethanol consumption and preference than parent rats during intermittent-access testing. There were not differences, however, between IAT/IANT congenic and parent rats during intermittent access. These data support the hypothesis that there is a genetic relationship between initial ethanol sensitivity and ethanol consumption, at least for the IHAS/ILAS-derived congenic rats. Our current studies, however, cannot eliminate pharmacokinetic or taste preference factors as contributing to the rats' responses, nor can we eliminate the possibility of a linkage effect because of the fairly large size of the QTL intervals; i.e., distinct genes may be mediating the acute sensitivity and drinking responses.

Dissecting operant alcohol self‐administration using saccharin‐fading procedure

“…These data are similar to those obtained by other studies in which the percentage of alcohol was increased 16,20,30 . On the contrary, at the end of the alcohol concentration increase (10% alcohol) there was a significant decrease in consumption, similar to that described in other studies 31 . Concerning this, the results depicted in Figure 3C could explain this data.…”

“…16,20,30 On the contrary, at the end of the alcohol concentration increase (10% alcohol) there was a significant decrease in consumption, similar to that described in other studies. 31 Concerning this, the results depicted in Figure 3C could explain this data. This figure shows that the increase in the percentage of alcohol is accompanied by an increase in the responses/rewards ratio.…”

High-fructose diet initiated during adolescence does not affect basolateral amygdala excitability or affective-like behavior in Sprague Dawley rats

“…This genetic variation may be of use in future studies investigating genetic susceptibility to a metabolic insult. Indeed, contrasting control and disease-model genomes using QTL mapping has identified genetic loci associated with alcohol-seeking behavior [59], anxietyand depression-like behavior [60,61], and diabetes [62] in various rodent models. Contrasting Sprague Dawley and Wistar rats in a similar manner may identify genetic loci associated with pathological responses to dietary fructose.…”

Alcohol Sensitivity as an Endophenotype of Alcohol Use Disorder: Exploring Its Translational Utility between Rodents and Humans

“…Mice and rats have a righting reflex that corrects the orientation of their body when taken out of its normal, upright position. Given that ethanol is a central nervous system depressant that produces sedative–hypnotic effects on behavior, LORR can be used to estimate hypnotic sensitivity to ethanol in rodents and has been shown to be genetically influenced [ 83 , 85 , 108 , 182 , 183 , 185 , 198 , 199 , 200 , 201 , 202 , 203 , 204 , 205 , 206 ]. The LORR paradigm entails injecting animals with an anesthetic dose of ethanol, placing them on their backs in a V-shaped trough, and recording the amount of time it takes to regain the righting reflex as well as BEC at recovery [ 85 ].…”

“…Multiple studies have examined the genetic relationship between LORR sensitivity and ethanol consumption in rodents [ 116 , 188 , 203 ]. For example, selectively bred mice that consume large amounts of ethanol (HDID-1 mice [ 78 ]) are significantly less sensitive than controls to ethanol’s sedative–hypnotic effects [ 188 ].…”